Synthesis and conformational analysis of naphth[1,2-e][1,3]oxazino[4,3-a][1,3]isoquinoline and naphth[2,1-e][1,3]oxazino[4,3-a]isoquinoline derivatives

Article abstract of DOI:10.1016/j.tet.2008.05.025

Through the cyclization of 1-(β-hydroxynaphthyl)-1,2,3,4-tetrahydroisoquinoline and 1-(α-hydroxynaphthyl)-1,2,3,4-tetrahydroisoquinoline with formaldehyde, phosgene, p-nitrobenzaldehyde or p-chlorophenyl isothiocyanate, 8-substituted 10,11-dihydro-8H,15bH

Full text of DOI:10.1016/j.tet.2008.05.025

Tetrahedron 64 (2008) 7378–7385
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and conformational analysis of naphth[1,2-e][1,3]oxazino[4,3-a]-
[1,3]isoquinoline and naphth[2,1-e][1,3]oxazino[4,3-a]isoquinoline
derivatives
a
a
b
b
a,
*
´
´
¨ ¨
Matthias Heydenreich , Andreas Koch , Istvan Szatmari , Ferenc Fulop , Erich Kleinpeter
a Department of Chemistry, University of Potsdam, Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam-Golm, Germany
b Institute of Pharmaceutical Chemistry and the Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eo¨tvo¨s utca 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Through the cyclization of 1-(b-hydroxynaphthyl)-1,2,3,4-tetrahydroisoquinoline and 1-(a-hydroxy-
Received 18 April 2008
Received in revised form 8 May 2008
Accepted 8 May 2008
naphthyl)-1,2,3,4-tetrahydroisoquinoline with formaldehyde, phosgene, p-nitrobenzaldehyde or
p-chlorophenyl isothiocyanate, 8-substituted 10,11-dihydro-8H,15bH-naphth[1,2-e][1,3]oxazino[4,3-a]-
isoquinolines (3 and 4) and 10,11-dihydro-8H,15bH-naphth[2,1-e][1,3]oxazino[4,3-a]isoquinolines (15 and
16) were prepared. Conformational analysis of both the piperidine and the 1,3-oxazine moieties of these
heterocycles by NMR spectroscopy and an accompanying theoretical study revealed that these two
conformationally flexible six-membered ring moieties prefer twisted chair conformers.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 11 May 2008
Keywords:
Isoquinolines
Naphthoxazines
Synthesis
Conformational analysis
Theoretical calculations
NMR spectroscopy
1. Introduction
2. Results and discussion
In consequence of their valuable biological activity and wide-
ranging potential for synthetic applications, considerable interest
has been demonstrated in partially saturated isoquinolines.1 Recent
systematic studies on tricyclic derivatives of saturated isoquinoline
derivatives containing another saturated heteroring, bearing dif-
ferent substituents at positions 1, 2, and 4 (1,3-oxazino[4,3-a]-,2
1,2,3-oxathiazino[4,3-a]-,3 1,3,2-oxaphosphorino[4,3-a]-,4 1,3,2-
diazaphosphorino[6,1-a]-,5 1,3,4-diazaphosphino[5,4-a]-, and 1,3,4-
diazaphosphino[4,5-b]isoquinolines6), led to the conclusion that
the heteroatoms, the substituents on the partly saturated hetero-
cyclic rings, and the configurations of the substituted carbon atoms
exert pronounced effects on the conformational equilibria of these
compounds.
Our present aims were to investigate the influence of
a naphthalene ring annelated to positions 1, 2 of naphth[1,2-e]-
[1,3]oxazino[4,3-a]isoquinoline and naphth[2,1-e]oxazino[4,3-a]iso-
quinoline and to study the effects of different substituents (oxo,
p-nitrophenyl, and phenylimino) at position 8 on the conformations
of these conformationally flexible heterocyclic ring systems.
2.1. Syntheses
The ring-closure reaction of 1-substituted 1,2,3,4-tetrahy-
droisoquinoline 1,3-amino alcohols with one-carbon fragments is a
common method for the synthesis of 1,3-oxazino[4,3-a]isoquino-
lines. This transformation is often applied for homocalycotomines,
bearing substituents in the side-chain, for the purpose of de-
termining the configuration of the substituted atoms in the rigid
ring-closed products.2e,7
The starting materials, 1-(
b
-hydroxynaphthyl)-1,2,3,4-tetrahy-
droisoquinolines (1 and 2)8 and 1-(
a-hydroxynaphthyl)-1,2,3,4-
tetrahydroisoquinolines (13 and 14),8 were prepared by the reaction
of 2- or 1-naphthol with the corresponding 3,4-dihydroisoquino-
line derivative according to a method published previously.8a
Under mild conditions, the treatment of 1-hydroxynaphthyl-
tetrahydroisoquinolines 1, 2, 13, and 14 with formaldehyde
led to 8-unsubstituted 10,11-dihydro-8H,15bH-naphth[1,2-e][1,3]-
oxazino[4,3-a]isoquinolines (3 and 4, Scheme 1) and 10,11-dihydro-
8H,15bH-naphth[2,1-e]oxazino[4,3-a]isoquinolines (15 and 16,
Scheme 2). An oxo group could be inserted at position 8 by the
treatment of 1, 2, 13 or 14 with phosgene in the presence of triethyl-
amine at room temperatureyielding5, 6 (Scheme 1),17 or 18 (Scheme
2), respectively.
* Corresponding author. Tel.: þ49 331 997 5210; fax: þ49 331 977 5064.
E-mail address: kp@chem.uni-potsdam.de (E. Kleinpeter).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.025

M. Heydenreich et al. / Tetrahedron 64 (2008) 7378–7385
7379
12
11
11a
13
14
R
R
R
R
R
10
9
15b
N
NH
N
O
8
15a
CH2O
R
COCl2
15
1
7
O
OH
O
2
3
6a
6
4a
4
5
R = OMe: 3
R = OMe: 1
R = H: 2
R = OMe: 5
R = H: 6
R = H: 4
CHO
SCN
O2N
Cl
Cl
R
R
NO2
R
R
R
S
H
H
O
N
N
N
N
N
H
R
O
OH
1. MeI
2. KOH
Cl
R = OMe: 7
R = H: 8
R = OMe: 11
R = H: 12
R = OMe: 9
R = H: 10
Scheme 1.
Through the reactions of 1, 2, 13, and 14 with p-nitro-
benzaldehyde, the p-nitrophenyl group could be inserted into po-
sition 8 (7 and 8, Scheme 1; 19 and 20, Scheme 2). In the latter
reactions, the formation of C-8 epimeric pairs is possible, but the
NMR spectra of the crude product revealed the formation of only
one diastereomer. Interestingly, the NMR investigations (vide infra)
indicated that the corresponding diastereomers contain H-8 and H-
15b in the trans position in 7 and 8, and in the cis position in 19 and
20. Thus, different diastereoselectivities are involved in the reaction
pathways to the new 8-p-nitrophenyl-substituted 10,11-dihydro-
8H,15bH-naphth[1,3]oxazino[4,3-a]isoquinolines (7, 8, 19, and 20,
cf. Schemes 1 and 2).
For the preparation of 8-(p-chlorophenylimino)-substituted
10,11-dihydro-8H,15bH-naphth[1,3]oxazino[4,3-a]isoquinolines 11,
12 (Scheme 1), 23, and 24 (Scheme 2), 1-hydroxynaphthyltetrahy-
droisoquinolines 1, 2, 13 or 14 were reacted with p-chlorophenyl
isothiocyanate. Thioureas 9, 10, 21, and 22 were converted with
methyl iodide to the corresponding S-methyl isothiourea
derivatives, and subsequent treatment with methanolic KOH gave
the desired 8-(p-chlorophenylimino)-substituted derivatives (11
and 12, Scheme 1; 23 and 24, Scheme 2) via methyl mercaptan
elimination.
2.2. Conformational analysis
For the compounds studied, theoretical calculations were per-
formed for all the stereoisomers [the different configurations (S/R)
at C-15 and N-9 (i.e., the cis/trans isomers of the 9-azadecalin
moiety), and possible conformations (twisted chair or boat) of the
two six-membered heterocyclic ring moieties]; in this way, the
global minimum-energy structures were determined.
For 3 and 4, both the theoretical calculations and the NMR
spectroscopic study revealed the conformational equilibria of two
conformers each. The energies of the participating conformers
were calculated with consideration of the effect of the solvent
methylene chloride; this effect, however, proved to be only minor
(vide infra). For the other compounds studied, the global mini-
mum-energy structures are energetically so stable relative to the
next-following local minimum-energy structure that a consider-
ation of the solvent was neglected.
12
11
11a
13
R
R
R
R
10
9
14
15b
N
NH
OH
N
O
8
COCl2
15a
CH2O
R
R
15
7
O
O
1
2
6b
6a
6
5
2a
3
4
R = OMe: 15
R = H: 16
R = OMe: 13
R = H: 14
R = OMe: 17
R = H: 18
CHO
SCN
O2N
Cl
Cl
R
R
NO2
R
R
R
S
H
H
O
N
N
N
N
N
H
R
O
OH
1. MeI
Cl
2. KOH
R = OMe: 19
R = H: 20
R = OMe: 23
R = H: 24
R = OMe: 21
R = H: 22
Scheme 2.

7380
M. Heydenreich et al. / Tetrahedron 64 (2008) 7378–7385
Table 1
Conformational analyses were carried out by combining these
Calculated distances (in Å) between H-15b and H-10 (syn) and H-11 (syn),
respectively, in the compounds 3 and 4
theoretical calculations of the minimum-energy conformations (for
both 3 and 4, a second conformer was found to participate in the
conformational equilibria) with the experimental results obtained
from NMR measurements. Mainly the coupling constants and the
NOEs between H-15b and the other protons of the molecule proved
useful for the conformational studies. NOEs were extracted from
the 2D-NOESY NMR spectra; and the desired spatial information
was extracted from the corresponding theoretically calculated
distances of the corresponding protons in the global minimum-
energy structures (the two participating conformers for 3 and 4).
3a
3b
4a
4b
H-15b–H-10 (syn)
H-15b–H-11 (syn)
2.35
3.91
3.29
2.32
2.35
3.91
3.26
2.31
Table 2
Temperature dependence of experimentally determined vicinal coupling constants
(in Hz) between H-10 and H-11 in compound 3
3J(H,H)
Temperature
193 K
213 K
233 K
253 K
273 K
H-10 (syn)–H-11 (anti)a
H-10 (anti)–H-11 (syn)a
11.6
2.0
11.3
2.4
10.9
3.0
10.5
3.4
10.1
3.8
2.2.1. The (unsaturated) piperidine ring moiety
The conformation differs in the various products, depending on
the starting material (
a- or b-naphthol) and the substituent on the
a
Protons (syn/anti) assigned according to NOEs.
unsaturated oxazine ring.
Table 3
2.2.1.1. Compounds 3 and 4. In these two compounds, NOEs were
found between H-15b and H-10 (syn) and H-11 (syn), respectively.
In the global minimum-energy conformations (3a and 4a, cf. Fig. 1)
obtained, the piperidine moiety proved to be in a twisted chair
conformation with smaller distances between H-15b and H-10
(syn) than between H-15b and H-11 (syn) (cf. Table 1). As the cor-
responding NOEs are similar, this result can be explained only by
assuming the participation of the second, low-energy conformer
(3b and 4b) in the conformational equilibrium. This theoretically
found structure involves a boat conformation of the piperidine ring
moiety; it is slightly higher in energy [1.96 kcal/mol for 3 (2.21 kcal/
mol in CD2Cl2), 0.20 kcal/mol for 4 (both in the gas state and in
CD2Cl2)] and gives the expected smaller distance between H-15b
and the H-11 (syn) than that between H-15b and H-10 (syn) (cf.
Fig. 1).
To prove the assumption of the existence of two conformers in
equilibrium in solution if the interconversion process is fast on the
NMR time scale, the temperature dependence of any physico-
chemical property can be studied because the different conformers
have different energies. This was proved for the relevant vicinal
coupling constants by decreasing the temperature of the solution:
the corresponding values were observed to be temperature-de-
pendent changing with decreasing temperature in the direction of
the minimum-energy conformation (as shown for 3 in Table 2);
a similar dependence was found for 4. Decrease of the temperature
is accompanied by a decrease in the H-10 (syn)–H-11 (anti) and an
increase in the H-10 (anti)–H-11 (syn) vicinal H,H-coupling con-
stants (cf. Table 2), in line with the changes expected if the global
minimum structure is approached.
Calculated dihedral angles (in ꢁ) and vicinal coupling constants (in Hz) between
H-10 and H-11 in compound 3
3a
3b
H-10
H-10
H-10
H-10
(syn)–H-11
(anti)
(anti)–H-11
(syn)
(syn)–H-11
(anti)
(anti)–H-11
(syn)
Dihedral angle
(calcd)
155.5
ꢀ77.7
64.4
ꢀ167.8
3J(H,H) (calcd)a
11.9
1.5
1.8
13.1
a
Calculated by the method of Altona et al.9
[Jcalcd (3a)ꢀJcalcd (3b)], the free energy differences ꢀ
D
G0¼RT ln K for
the two participating conformers, and, via
D
G0¼
D
H0ꢀT
D
S0, the en-
thalpy difference between the two conformers [the value thus
obtained for
agreement with the theoreticallycalculated energy difference of the
two conformers: ꢀ2.21 kcal/mol (in CD2Cl2)].
D
H0¼ꢀ2.38 kcal/mol (
D
S0¼6 cal/mol K) is in good
2.2.1.2. Compounds 15 and 16. In the NMR spectra of 15 and 16, no
NOEs were found between H-15b and the protons in either position
10 or position 11. This is in excellent accordance with the theoret-
ical results, which indicate only one global minimum-energy
structure each, with a twisted chair conformation, as given in Fig-
ure 2. In agreement with the experimental findings, the calculated
distances between H-15b and H-10 (syn) (4.146 Å for 15 and 4.147 Å
for 16) and H-11 (syn) (4.187 Å for 15 and 4.180 Å for 16) were found
to be too long to generate NOE enhancements in the NMR spectra.
Table 3 reports the ab intio calculated dihedral angles between
the protons H-10 and H-11 for the two minimum-energy structures
of 3 (3a and 3b), which were applied to calculate the corresponding
vicinal coupling constants between the protons H-10 and H-11 in 3a
and 3b via the Altona equation.9 These values, finally, can be
employed to calculate the equilibrium constant K¼[Jexp.ꢀJcalcd (3b)]/
2.2.1.3. Compounds 7 and 8. A substituent at position 8 obviously
prevents the type of equilibrium observed for 3 and 4. The theo-
retical study indicated only one minimum-energy structure (H-8
and H-15b in trans position), a twisted chair conformer (cf. Fig. 3 for
8). However, in contrast with the twisted chair conformer in 15
and 16, NOEs were obtained and in good agreement with the
Figure 1. Minimum-energy conformation (left, 4a) and the conformation next higher in energy (4b) for 9S,15bS-4.

M. Heydenreich et al. / Tetrahedron 64 (2008) 7378–7385
7381
Figure 2. Minimum-energy conformation of 9S,15bS-15.
Figure 5. Minimum-energy conformation of 9S,15bS-5.
method, which successfully reproduces the experimental confor-
mation evidence.
2.2.1.5. Compounds 5, 6, 11, 12, 17, 18, 23, and 24. Introduction of
the sp2 carbon at position 8 obviously leads to very similar con-
formational behavior of this kind of compounds; in accordance
with this, very similar minimum-energy conformations of all of
them were calculated theoretically. These structures are charac-
terized by a twisted chair conformation of the piperidine ring
moiety, with short distances between H-15b and H-10 (syn), cor-
roborated excellently by the experimentally found NOE enhance-
ments. As an example, the global minimum-energy conformation
of 5 is given in Figure 5; the distance between H-15b and H-10 (syn)
in this case proved to be 2.297 Å.
2.2.2. The (unsaturated) oxazine ring moiety
Figure 3. Minimum-energy conformation of 8R,9S,15bS-8.
The conformation of the related unsaturated oxazine ring in the
compounds studied depends strongly on the hybridization of C-8.
In the compounds with an sp3 C-8, there is likewise a twisted-boat
conformation (cf. e.g., Fig. 4), while in compounds with an sp2-
hybridized C-8 the ring is nearly flat, with a slight boat conforma-
tion (cf. e.g., Fig. 5). This can be clearly seen from the different bond
angles C-8–N-9–C-15b, which have values of w111ꢁ in the former
case and w120ꢁ in the latter case.
Further, due to conjugation of the N-9 lone pair and the C(8)]O
carbonyl group, the carbamate fragments R2N–C(]O)–OR in these
compounds are almost planar; this is clearly demonstrated by the
sum of the bond angles C-8–N-9–C-10, C-10–N-9–C-15b, and C-
15b–N-9–C-8, which is 349ꢁ–351ꢁ in 5, 6, 11, 12, 17, 18, 23, and 24,
but only 335.8ꢁ–341.3ꢁ in the remaining compounds 3, 4, 7, 8,15,16,
19, and 20, where the pyramidality of the N-9, for example, the
configuration of the fused heterocyclic piperidine and oxazine ring
(in other words, the configuration of the substituted 9-azadecaline
moiety), can be characterized by the relative position of the lone
pair of N-9 and H-15b.2–6 In all naphthoxazinoisoquinolines con-
taining C-8 in sp3 hybridization the lone pair of N-9 and H-15b is in
the cis position.
corresponding distances in the calculated structures, e.g., for 7 an
H-15b–H-10 (syn) distance of 2.266 Å and an H-8–H-11 (anti) dis-
tance of 2.619 Å.
2.2.1.4. Compounds 19 and 20. For these compounds (H-8 and H-
15b in cis position), boat conformations were calculated, as depic-
ted in Figure 4 for 19. In complete agreement with the calculated
distances between H-15b and H-8 (2.323 Å for 19 and 2.320 Å for
20), and between H-10 (syn) and H-20 of the p-nitrophenyl sub-
stituent (2.933 Å for 19 and 2.953 Å for 20), the corresponding
significant NOEs detected lend further support to the theoretical
3. Conclusions
A series of napth[1,2-e]- and naphth[2,1-e][1,3]oxazino[4,3-a]-
isoquinoline derivatives with both sp3 (3, 4, 7, 8, 15, 16, 19, and 20)
and sp2 hybridization of C-8 (5, 6,11,12,17,18, 23, and 24) have been
synthesized by the cyclization of 1-(
b-hydroxynaphthyl)- or 1-
(a
-hydroxynaphthyl)-1,2,3,4-tetrahydroisoquinoline, respectively,
with formaldehyde, phosgene, p-nitrobenzaldehyde or p-chloro-
phenyl isothiocyanate. The conformational analyses revealed that
(except for 15 and 16) the compounds exhibit a twisted chair
Figure 4. Global minimum-energy conformation of 8S,9S,15bS-19.

7382
M. Heydenreich et al. / Tetrahedron 64 (2008) 7378–7385
conformation. Compounds 3 and 4 additionally display the corre-
sponding boat conformation in their conformational equilibria. The
twisted chair conformations, however, are not the same in all the
compounds studied: the minimum-energy conformations of 15 and
16 are characterized by C-10 being below the virtual ring plane, in
contrast with the other compounds, where C-10 is above the same
plane. Moreover, the stereochemistry differs in compounds 7, 8,
4.2.1. Compound 3
Reaction time: 6 h; yield: 0.35 g (55%). Mp 148–150 ꢁC. 1H NMR
d
7.78 (m, 2H, H-1 and H-4), 7.73 (d, J¼8.8 Hz, 1H, H-5), 7.45 (t,
J¼7.5 Hz,1H, H-2), 7.34 (t, J¼7.3 Hz,1H, H-3), 7.12 (d, J¼8.8 Hz,1H, H-
6), 6.67 (s, 1H, H-12), 6.52 (s, 1H, H-15), 5.54 (s, 1H, H-15b), 4.75 (d,
J¼ꢀ6.8 Hz, 1H, H-8), 4.69 (d, J¼ꢀ6.8 Hz, 1H, H-8), 3.86 (s, 3H, OMe-
13), 3.79 (m, 1H, H-10), 3.35 (s, 3H, OMe-14), 3.20 (m,1H, H-10), and
19, and 20, with a substituent at position 8; 7 and 8 have the R
configuration, and 19 and 20 the S configuration at this position.
*
2.86 (m, 2H, H-11); 13C NMR
d 150.8 (C-6a),148.0 (C-13),147.1 (C-14),
*
132.7 (C-15d), 129.3 (C-5), 128.9 (C-4a), 128.9 (C-15a), 128.6 (C-4),
126.3 (C-2), 123.3 (C-3), 123.1 (C-1), 123.1 (C-11a), 118.9 (C-6), 114.9
(C-15c), 112.6 (C-15), 111.5 (C-12), 78.2 (C-8), 55.9 (OMe-13), 55.6
(OMe-14), 54.3 (C-15b), 47.1 (C-10), and 24.9 (C-11). Anal. Calcd for
This may be due to the differing degrees of steric hindrance
encountered during the syntheses.
4. Experimental
C22H21NO3:C, 76.06;H, 6.09;N, 4.03. Found:C, 75.93;H, 6.12;N, 4.09.
4.1. General remarks
4.2.2. Compound 4
Reaction time: 7 h; yield: 0.43 g (82%). Mp 168–170 ꢁC. 1H NMR
Melting points were determined on a Kofler micro melting ap-
paratus and are uncorrected. Merck Kieselgel 60 F254 plates were
used for TLC. 1H and 13C NMR spectra were recorded in CDCl3
(unless specified as CD2Cl2 or DMSO-d6) solution in 5 mm tubes, at
room temperature, on a 500 MHz NMR spectrometer at 500.17 (1H)
and 125.78 (13C) MHz, with the deuterium signal of the solvent as
the lock and TMS as the internal standard for 1H or the solvent as
the internal standard for 13C. All spectra (1H, 13C, gs-H,H-COSY,
gs-HMQC, gs-1D-HMQC, gs-HMBC, and NOESY) were acquired and
processed with the standard software. In cases involving strong
overlapping of the 1H signals, the PERCH10 software was used to
extract the coupling constants. Quantum chemical calculations
were carried out with the program package GAUSSIAN 03 version
C.02.11 Different conformations and configurations of the studied
compounds were preoptimized with the PM3 Hamiltonian.12 The
B3LYP density functional method was selected for all calculations.
The method was based on Becke’s three-parameter hybrid func-
tionals13 and the correlation functional of Lee et al.14 A moderate
d
7.80 (d, J¼7.8 Hz, 1H, H-4), 7.73 (d, J¼8.9 Hz, 1H, H-5), 7.67 (d,
J¼8.4 Hz, 1H, H-1), 7.42 (t, J¼8.3 Hz, 1H, H-2), 7.35 (t, J¼8.0 Hz, 1H,
H-3), 7.20 (m, 3H, H-12, H-13, and H-14), 7.12 (d, J¼8.9 Hz, 1H, H-6),
6.87 (d, J¼7.7 Hz, 1H, H-15), 5.54 (s, 1H, H-15b), 4.62 (m, 2H, H-8),
3.85 (ddd, J¼ꢀ13.0, 7.7, and 7.0 Hz, 1H, H-10), 3.03 (ddd, J¼ꢀ13.0,
6.2, and 6.9 Hz,1H, H-10), 2.96 (ddd, J¼ꢀ10.9, 6.2, and 7.0 Hz,1H, H-
11), and 2.96 (ddd, J¼ꢀ10.9, 7.7, and 6.9 Hz, 1H, H-11); 13C NMR
d
150.9 (C-6a), 137.1 (C-11a), 134.4 (C-15a), 132.8 (C-15d), 129.3 (C-
5), 128.9 (C-15), 128.8 (C-4a), 128.5 (C-4), 128.3 (C-12), 127.1 (C-13),
126.6 (C-2), 126.1 (C-14), 123.3 (C-3), 123.0 (C-1), 118.8 (C-6), 114.3
(C-15c), 78.6 (C-8), 54.3 (C-15b), 46.7 (C-10), and 25.8 (C-11). Anal.
Calcd for C20H17NO: C, 83.60; H, 5.96; N, 4.87. Found: C, 83.48; H,
6.02; N, 5.91.
4.2.3. Compound 15
Reaction time: 8 h; yield: 0.30 g (68%). Mp 218–219 ꢁC. 1H NMR
8.17 (d, J¼7.3 Hz, 1H, H-6), 7.70 (d, J¼7.1 Hz, 1H, H-3), 7.44 (m, 2H,
d
H-4 and H-5), 7.25 (d, J¼8.8 Hz, 1H, H-2), 7.22 (d, J¼8.6 Hz, 1H, H-1),
6.90 (s, 1H, H-5), 6.66 (s, 1H, H-12), 5.48 (s, 1H, H-15b), 5.47 (d,
J¼10.0 Hz,1H, H-8), 5.18 (d, J¼9.5 Hz,1H, H-8), 3.98 (s, 3H, OMe-14),
3.87 (s, 3H, OMe-13), 3.25 (ddd, J¼ꢀ11.9, 11.8, and 4.5 Hz, 1H, H-10),
3.14 (ddd, J¼ꢀ11.9, 6.6, and 1.7 Hz, 1H, H-10), 3.08 (ddd, J¼ꢀ16.2,
11.8, and 6.6 Hz, 1H, H-11), and 2.66 (ddd, J¼ꢀ16.2, 4.5, and 1.7 Hz,
split valence basis set 6-31G
15 was used because of the size of the
*
studied compounds. Polarization functions on H atoms were not
used because no H-bonds exist in this series. All optimizations were
carried out without any restriction at this B3LYP/6-31G level of
*
theory. The self-consisted reaction field (SCRF) method and the
self-consisted isodensity polarized continuum model (SCIPCM)
1H, H-11); 13C NMR
d 148.3 (C-13), 147.5 (C-6b), 146.7 (C-14), 133.4
were used at the B3LYP/6-31G
solvent; the dielectric constant
calculations.
*
level of theory to consider the
of CDCl3, 4.18, was used in the
(C-2a), 127.4 (C-3), 126.3 (C-11a or C-15a), 126.2 (C-15a or C-11a),
126.0 (C-4), 125.2 (C-5), 125.1 (C-1), 124.4 (C-6a), 121.7 (C-6), 119.3
(C-2), 116.0 (C-15c), 112.8 (C-15), 111.8 (C-12), 84.7 (C-8), 57.2 (C-
15b), 56.2 (OMe-14), 55.8 (OMe-13), 43.2 (C-10), and 28.6 (C-11).
Anal. Calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C,
76.13; H, 6.03; N, 4.11.
3
Visualization was carried out with the modeling software SYBYL
7.316 and the program GaussView 2.0.17 Results were calculated on
an SGI and on a Linux cluster.
Compounds 1, 2, 13, and 14 were prepared according to pro-
cedures reported in the literature.8 General procedures for the
synthesis of other compounds (3–12 and 15–24) follow.
4.2.4. Compound 16
Reaction time: 7 h; yield: 0.38 g (73%). Mp 186–188 ꢁC. 1H NMR
d
8.17 (d, J¼7.4 Hz, 1H, H-6), 7.59 (d, J¼7.2 Hz, 1H, H-3), 7.43 (m, 2H,
4.2. General method for the synthesis of 13,14-dimethoxy-
10,11-dihydro-8H,15bH-naphth[1,2-e][1,3]oxazino[4,3-a]-
isoquinoline (3), 10,11-dihydro-8H,15bH-naphth[1,2-e]-
[1,3]oxazino[4,3-a]isoquinoline (4), 13,14–10,11-dihydro-
8H,15bH-dimethoxynaphth[2,1-e][1,3]oxazino[4,3-a]-
isoquinoline (15), and 10,11-dihydro-8H,15bH-naphth[2,1-e]-
[1,3]oxazino[4,3-a]isoquinoline (16)
H-4 and H-5), 7.40 (d, J¼7.3 Hz, 1H, H-15), 7.30 (t, J¼7.0 Hz, 1H, H-
14), 7.26 (t, J¼7.5 Hz, 1H, H-13), 7.24 (m, 1H, H-2), 7.18 (m, 2H, H-1
and H-12), 5.57 (s, 1H, H-15b), 5.47 (d, J¼ꢀ9.9 Hz, 1H, H-8), 5.19 (d,
J¼ꢀ9.9 Hz, 1H, H-8), 3.30 (m, 1H, H-10), 3.15 (m, 2H, H-10 and H-
11), and 2.75 (m, 1H, H-11); 13C NMR
d 147.7 (C-6b), 134.2 (C-11a),
133.4 (2C, C-2a and C-15a), 129.8 (C-15), 129.5 (C-12), 127.4 (C-3 or
C-13), 127.3 (C-13 or C-3), 126.1 (C-4), 125.2 (3C, C-1, C-5, and C-14),
124.4 (C-6a), 121.7 (C-6), 119.2 (C-2), 115.8 (C-15C), 84.7 (C-8), 57.6
(C-15b), 43.3 (C-10), and 29.0 (C-11). Anal. Calcd for C20H17NO: C,
83.60; H, 5.96; N, 4.87. Found: C, 83.73; H, 5.88; N, 4.91.
To
a stirred solution of the 1-hydroxynaphthyltetrahy-
droisoquinoline 1, 2, 13 or 14 (1.82 mmol) in toluene (25 mL), 40%
aqueous formaldehyde (0.2 mL, 2.66 mmol) was added. The mix-
ture was stirred at room temperature until TLC indicated the
absence of the starting material (the reaction times are shown
individually for all compounds). The solution was then dried with
Na2SO4, the solvent was evaporated off, the crude product was
crystallized from Et2O, and recrystallized from i-Pr2O–EtOAc (3:1).
4.3. General method for the synthesis of 13,14-dimethoxy-
10,11-dihydro-8H,15bH-naphth[1,2-e][1,3]oxazino[4,3-a]-
isoquinolin-8-one (5), 10,11-dihydro-8H,15bH-naphth[1,2-e]-
[1,3]oxazino[4,3-a]isoquinolin-8-one (6), 13,14-dimethoxy-

M. Heydenreich et al. / Tetrahedron 64 (2008) 7378–7385
7383
10,11-dihydro-8H,15bH-naphth[2,1-e][1,3]oxazino[4,3-a]-
isoquinolin-8-one (17), and 10,11-dihydro-8H,15bH-
naphth[2,1-e][1,3]oxazino[4,3-a]isoquinolin-8-one (18)
H-12 and H-13), 7.13 (td, J¼7.1 and 1.9 Hz, 1H, H-14), 7.06 (d,
J¼7.7 Hz, 1H, H-15), 5.79 (s, 1H, H-15b), 4.40 (ddd, J¼ꢀ12.7, 6.8, and
5.7 Hz, H-10), 3.58 (ddd, J¼ꢀ13.0, 8.6, and 6.0 Hz, 1H, H-10), 3.32
(ddd, J¼ꢀ16.1, 8.0, and 7.9 Hz, 1H, H-11), and 2.97 (dt, J¼ꢀ16.4 and
1-Hydroxynaphthyltetrahydroisoquinoline 1, 2, 13 or 14
(1.82 mmol) was suspended in toluene–H2O (20:20 mL), and Et3N
(0.74 g, 7.3 mmol) and phosgene (2.5 mL, 20%in toluene, 2.73 mmol)
were added. The mixture was stirred at room temperature until TLC
showed no more starting material, and EtOAc (40 mL) and H2O
(40 mL) were then added. The organic layer was separated, dried
(Na2SO4), and evaporated. The oily residue crystallized on treatment
with n-hexane (20 mL). The crystalline product was filtered off and
recrystallized from n-hexane–i-Pr2O (1:1).
5.6 Hz,1H, H-11); 13C NMR
d 150.6 (C-8),145.0 (C-6b), 136.3 (C-15a),
134.8 (C-11a), 133.8 (C-2a), 129.0 (C-12), 127.9 (C-13), 127.5 (C-3),
127.2 (C-4), 126.7 (C-5), 126.3 (C-14), 124.6 (C-15), 124.1 (C-1), 123.5
(C-2), 123.3 (C-6a), 121.5 (C-6), 112.9 (C-15c), 56.7 (C-15b), 43.9 (C-
10), and 26.9 (C-11). Anal. Calcd for C20H15NO2: C, 79.72; H, 5.02; N,
4.65. Found: C, 79.67; H, 5.05; N, 4.67.
4.4. General method for the synthesis of (8R
nitrophenyl)-13,14-dimethoxy-10,11-dihydro-8H,15bH-
naphth[1,2-e][1,3]oxazino[4,3-a]isoquinoline (7), (8R ,15bS
8-(4-nitrophenyl)-10,11-dihydro-8H,15bH-naphth[1,2-e]-
[1,3]oxazino[4,3-a]isoquinoline (8), (8S ,15bS )-8-(4-
*
,15bS
*
)-8-(4-
*
*
)-
4.3.1. Compound 5
Reaction time: 25 h; yield: 0.33 g (51%). Mp 183–185 ꢁC. 1H NMR
*
*
d
7.91 (d, J¼8.2 Hz, 1H, H-4), 7.89 (d, J¼8.9 Hz, 1H, H-5), 7.76 (d,
nitrophenyl)-13,14-dimethoxy-10,11-dihydro-8H,15bH-
naphth[2,1-e][1,3]oxazino[4,3-a]isoquinoline (19), and
J¼8.4 Hz, 1H, H-1), 7.57 (t, J¼7.6 Hz, 1H, H-2), 7.50 (t, J¼7.5 Hz, 1H,
H-3), 7.28 (d, J¼8.9 Hz,1H, H-6), 6.73 (s,1H, H-12), 6.18 (s,1H, H-15),
6.12 (s, 1H, H-15b), 4.47 (ddd, J¼ꢀ12.8, 7.6, and 4.8 Hz, 1H, H-10),
3.85 (s, 3H, OMe-13), 3.61 (ddd, J¼ꢀ13.1, 9.1, and 6.4 Hz, 1H, H-10),
3.38 (ddd, J¼ꢀ16.5, 8.2, and 8.2 Hz, 1H, H-11), 3.30 (s, 3H, OMe-14),
(8S
*
,15bS )-8-(4-nitrophenyl)-10,11-dihydro-8H,15bH-
*
naphth[2,1-e][1,3]oxazino[4,3-a]isoquinoline (20)
1-Hydroxynaphthyltetrahydroisoquinoline 1, 2, 13 or 14
(1.82 mmol) was heated at 55 ꢁC with an equimolar amount of p-
nitrobenzaldehyde (0.28 g, 1.28 mmol) in dry toluene (30 mL).
When no more starting material could be detected on TLC, the
solvent was evaporated off; the residual oil crystallized on treat-
ment with Et2O. The crystalline product was filtered off and
recrystallized from i-Pr2O–EtOAc.
and 2.95 (ddd, J¼ꢀ16.1, 5.7, and 5.1 Hz, 1H, H-11); 13C NMR
d 150.7
(C-8), 148.7 (C-13), 147.8 (C-6a), 147.1 (C-14), 130.6 (C-15d or C-4a),
130.5 (C-4a or C-15d), 130.5 (C-5), 128.9 (C-4), 128.3 (C-15a), 127.4
(C-2),126.8 (C-11a),125.2 (C-3),123.1 (C-1),117.2 (C-6),112.0 (C-12),
111.9 (C-15c), 109.3 (C-15), 56.0 (OMe-13), 55.7 (OMe-14), 54.7 (C-
15b), 44.6 (C-10), and 26.1 (C-11). Anal. Calcd for C22H19NO4: C,
73.12; H, 5.30; N, 3.88. Found: C, 73.25; H, 5.27; N, 3.91.
4.4.1. Compound 7
4.3.2. Compound 6
Reaction time: 75 h; yield: 0.58 g (68%). Mp 207–209 ꢁC. 1H
Reaction time: 25 h; yield: 0.34 g (62%). Mp 248–250 ꢁC. 1H
NMR
d
8.31 (d, J¼8.7 Hz, 2H, H-30), 7.81 (d, J¼8.6 Hz, 2H, H-20), 7.79
NMR (CD2Cl2)
d
7.93 (d, J¼7.6 Hz, 1H, H-4), 7.92 (d, J¼9.4 Hz, 1H, H-
(m, 2H, H-1 and H-4), 7.76 (d, J¼8.9 Hz, 1H, H-5), 7.51 (td, J¼7.7 and
0.7 Hz, 1H, H-2), 7.40 (t, J¼7.6 Hz, 1H, H-3), 7.08 (d, J¼8.9 Hz, 1H, H-
6), 6.69 (s, 1H, H-12), 6.55 (s, 1H, H-15), 5.79 (s, 1H, H-8), 5.77 (s, 1H,
H-15b), 3.88 (s, 3H, OMe-13), 3.52 (ddd, J¼ꢀ14.3, 11.4, and 6.4 Hz,
1H, H-10), 3.35 (s, 3H, OMe-14), 2.85 (ddd, J¼ꢀ14.3, 7.0, and 2.4 Hz,
1H, H-10), 2.81 (ddd, J¼ꢀ17.2, 11.4, and 7.0 Hz, 1H, H-11), and 2.64
5), 7.69 (d, J¼8.4 Hz, 1H, H-1), 7.56 (td, J¼7.2 and 1.2 Hz, 1H, H-2),
7.52 (td, J¼7.8 and 1.0 Hz, 1H, H-3), 7.26 (d, J¼7.9 Hz, 1H, H-12), 7.25
(d, J¼9.0 Hz, 1H, H-6), 7.21 (t, J¼7.4 Hz, 1H, H-13), 6.93 (t, J¼7.5 Hz,
1H, H-14), 6.55 (d, J¼7.8 Hz, 1H, H-15), 5.31 (s, 1H, H-15b), 4.31
(ddd, J¼ꢀ13.1, 7.3, and 6.1 Hz,1H, H-10), 3.68 (ddd, J¼ꢀ13.1, 7.8, and
6.9 Hz, 1H, H-10), 3.36 (ddd, J¼ꢀ16.6, 7.8, and 7.3 Hz, 1H, H-11), and
3.08 (ddd, J¼ꢀ16.6, 6.1, and 6.9 Hz, 1H, H-11); 13C NMR (CD2Cl2)
(ddd, J¼ꢀ17.2, 6.4, and 2.4 Hz, 1H, H-11); 13C NMR
d 150.4 (C-6a),
148.7 (C-40), 148.1 (C-13), 147.3 (C-14), 145.0 (C-10), 132.4 (C-15d),
129.5 (C-20), 128.9 (C-4 or C-5), 128.6 (C-5 or C-4), 128.6 (C-4a),
128.3 (C-15a), 126.4 (C-2), 125.3 (C-11a), 123.8 (C-30), 123.5 (C-3),
122.9 (C-1), 118.4 (C-6), 114.7 (C-15c), 112.4 (C-15), 111.7 (C-12), 86.6
(C-8), 55.9 (OMe-13), 55.6 (C-15b), 55.6 (OMe-14), 46.4 (C-10), and
23.8 (C-11). Anal. Calcd for C28H24N2O5: C, 71.78; H, 5.16; N, 5.98.
Found: C, 71.59; H, 5.20; N, 5.91.
d
150.5 (C-8), 148.2 (C-6a), 137.0 (C-15a), 135.3 (C-11a), 131.0 (C-
15d), 130.8 (2C, C-4a and C-5), 129.2 (C-12), 129.0 (C-4), 128.3 (C-
13), 127.9 (C-2), 126.3 (C-14), 125.4 (C-15), 125.2 (C-3), 123.4 (C-1),
117.3 (C-6), 112.0 (C-15c), 54.9 (C-15b), 44.4 (C-10), and 26.8 (C-11).
Anal. Calcd for C20H15NO2: C, 79.72; H, 5.02; N, 4.65. Found: C,
79.85; H, 5.07; N, 4.71.
4.3.3. Compound 17
4.4.2. Compound 8
Reaction time: 20 h; yield: 0.37 g (56%). Mp 199–201 ꢁC. 1H NMR
Reaction time: 50 h; yield: 0.48 g (64%). Mp 204–206 ꢁC.1H NMR
d
8.31 (m,1H, H-6), 7.86 (m,1H, H-3), 7.70 (d, J¼8.2 Hz,1H, H-2), 7.56
d
8.29 (d, J¼8.7 Hz, 2H, H-30), 7.83 (d, J¼8.1 Hz,1H, H-4), 7.75 (m, 4H,
(m, 2H, H-4 and H-5), 7.38 (d, J¼8.2 Hz, 1H, H-1), 6.70 (s, 1H, H-12),
6.61 (s, 1H, H-15), 5.72 (s, 1H, H-15b), 4.46 (ddd, J¼ꢀ13.0, 6.6, and
4.0 Hz, 1H, H-10), 3.86 (s, 3H, OMe-13), 3.68 (s, 3H, OMe-14), 3.51
(ddd, J¼ꢀ13.0, 9.8, and 5.6 Hz,1H, H-10), 3.31 (ddd, J¼ꢀ16.3, 9.8, and
6.6 Hz,1H, H-11), and 2.87 (ddd, J¼ꢀ16.3, 5.6, and 4.0 Hz,1H, H-11);
H-1, H-5, and H-20), 7.48 (t, J¼7.7 Hz,1H, H-2), 7.38 (t, J¼7.5 Hz,1H, H-
3), 7.21 (m, 2H, H-12 and H-13), 7.07 (d, J¼8.9 Hz, 1H, H-6), 7.03 (t,
J¼7.2 Hz, 1H, H-14), 6.94 (d, J¼7.8 Hz, 1H, H-15), 5.78 (s, 1H, H-15b),
5.70 (s, 1H, H-8), 3.53 (J¼ꢀ14.1, 10.3, and 6.6 Hz, 1H, H-10), 2.86
(J¼ꢀ17.2, 10.3, and 7.0 Hz, 1H, H-11), 2.78 (J¼ꢀ14.1, 7.0, and 3.6 Hz,
1H, H-10), and 2.77 (J¼ꢀ17.2, 6.6, and 3.6 Hz, 1H, H-11); 13C NMR
13C NMR
d 150.7 (C-8), 148.6 (C-13), 147.3 (C-14), 145.0 (C-6b), 133.7
(C-2a), 127.9 (C-15a), 127.5 (C-3), 127.1 (C-4 or C-5), 126.9 (C-11a),
126.8 (C-5 or C-4), 123.8 (C-1), 123.5 (C-2), 123.4 (C-6a), 121.5 (C-6),
113.5 (C-15c),112.0 (C-12),108.6 (C-15), 56.6 (C-15b), 55.9 (OMe-13),
55.9 (OMe-14), 44.2 (C-10), and 26.5 (C-11). Anal. Calcd for
d
150.4 (C-6a), 148.7 (C-40), 145.0 (C-10), 136.5 (C-15a), 133.8 (C-11a),
132.5 (C-15d), 129.5 (C-20), 129.0 (C-15), 128.9 (3C, C-4a, C-5, and C-
12), 128.6 (C-4), 127.3 (C-13), 126.9 (C-2), 126.4 (C-14), 123.8 (C-30),
123.5 (C-3),122.9 (C-1),118.4 (C-6),114.4 (C-15c), 86.9 (C-8), 55.6 (C-
15b), 46.4 (C-10), and 24.5 (C-11). Anal. Calcd for C26H20N2O3: C,
76.46; H, 4.94; N, 6.86. Found: C, 76.64; H, 4.87; N, 6.81.
C
22H19NO4: C, 73.12; H, 5.30; N, 3.88. Found: C, 73.17; H, 5.32; N, 3.91.
4.3.4. Compound 18
Reaction time: 30 h; yield: 0.38 g (70%). Mp 188–190 ꢁC. 1H NMR
4.4.3. Compound 19
d
8.31 (m, 1H, H-6), 7.87 (m, 1H, H-3), 7.71 (d, J¼8.4 Hz, 1H, H-2),
Reaction time: 24 h; yield: 0.63 g (74%). Mp 231–232 ꢁC. 1H NMR
7.56 (m, 2H, H-4 and H-5), 7.38 (d, J¼8.4 Hz, 1H, H-1), 7.24 (m, 2H,
d
8.36 (d, J¼8.2 Hz, 1H, H-6), 8.35 (d, J¼8.3 Hz, 2H, H-30), 8.05 (d,

7384
M. Heydenreich et al. / Tetrahedron 64 (2008) 7378–7385
J¼8.4 Hz, 2H, H-20), 7.77 (d, J¼8.0 Hz, 1H, H-3), 7.55 (ddd, J¼8.3, 7.0,
and 0.8 Hz, 1H, H-5), 7.50 (ddd, J¼8.1, 6.8, and 1.2 Hz, 1H, H-4), 7.37
(d, J¼8.6 Hz, 1H, H-2), 7.33 (d, J¼8.6 Hz, 1H, H-1), 6.98 (s, 1H, H-15),
6.65 (s, 1H, H-12), 6.51 (s, 1H, H-8), 5.76 (s, 1H, H-15b), 4.01 (s, 3H,
OMe-14), 3.87 (s, 3H, OMe-13), 2.89 (ddd, J¼ꢀ16.2, 12.0, and 6.3 Hz,
1H, H-11), 2.85 (ddd, J¼ꢀ12.0,12.0, and 4.3 Hz,1H, H-10), 2.71 (ddd,
J¼ꢀ12.0, 6.3, and 1.7 Hz, 1H, H-10), and 2.54 (ddd, J¼ꢀ16.2, 4.3, and
7.41 (m, 3H), 7.34 (d, J¼8.5 Hz, 1H), 7.25 (t, J¼7.5 Hz, 1H), 7.17 (d,
J¼7.7 Hz, 1H), 6.91 (s, 1H), 6.86 (d, J¼8.6 Hz, 1H), 6.54 (s, 1H), 4.54
(m,1H), 3.80 (s, 3H), 3.57 (s, 3H), 3.50 (m, 1H), 3.18 (m,1H), and 2.88
(m, 1H). Anal. Calcd for C28H25ClN2O3S: C, 66.59; H, 4.99; N, 5.55.
Found: C, 66.61; H, 4.95; N, 5.57.
4.5.4. Compound 22
1.7 Hz, 1H, H-11); 13C NMR
d
148.5 (C-13), 147.9 (C-40), 147.4 (C-6b),
Yield: 0.74 g (92%). Mp 204–206 ꢁC. 1H NMR (DMSO-d6)
d 10.31
146.9 (C-14),144.8 (C-10),133.5 (C-2a),127.7 (C-20),127.5 (C-3),126.8
(C-11a), 126.3 (C-5), 126.1 (C-15a), 125.6 (C-4), 124.9 (C-1), 124.4 (C-
6a), 123.5 (C-30), 121.5 (C-6), 120.3 (C-2), 116.5 (C-15c), 112.8 (C-15),
111.9 (C-12), 90.5 (C-8), 59.9 (C-15b), 56.3 (OMe-14), 55.8 (OMe-13),
37.2 (C-10), and 28.3 (C-11). Anal. Calcd for C28H24N2O5: C, 71.78; H,
5.16; N, 5.98. Found: C, 71.67; H, 5.15; N, 5.95.
(br s, 1H), 9.84 (br s, 1H), 8.31 (m, 1H), 7.81 (m, 1H), 7.52 (m, 2H),
7.40 (m, 3H), 7.34 (m, 2H), 7.29 (t, J¼7.5 Hz, 1H), 7.25 (t, J¼7.6 Hz,
1H), 7.18 (m, 2H), 7.01 (d, J¼7.7 Hz, 1H), 6.85 (d, J¼8.6 Hz, 1H), 4.62
(m, 1H), 3.60 (m, 1H), 3.23 (m, 1H), and 2.99 (m, 1H). Anal. Calcd for
C26H21ClN2OS: C, 70.18; H, 4.76; N, 6.30. Found: C, 70.23; H, 4.74; N,
6.28.
4.4.4. Compound 20
4.6. General method for the synthesis of 8-(4-
Reaction time: 24 h; yield: 0.52 g (70%). Mp 219–222 ꢁC. 1H NMR
chlorophenylimino)-13,14-dimethoxy-10,11-dihydro-8H,15bH-
naphth[1,2-e][1,3]oxazino[4,3-a]isoquinoline (11), 8-(4-
chlorophenylimino)-10,11-dihydro-8H,15bH-naphth[1,2-e]-
[1,3]oxazino[4,3-a]isoquinoline (12), 8-(4-
chlorophenylimino)-13,14-dimethoxy-10,11-dihydro-8H,15bH-
naphth[2,1-e][1,3]oxazino[4,3-a]isoquinoline (23), and 8-(4-
chlorophenylimino)-10,11-dihydro-8H,15bH-naphth[2,1-e]-
[1,3]oxazino[4,3-a]isoquinoline (24)
d
8.36 (d, J¼8.4 Hz, 1H, H-6), 8.34 (d, J¼8.8 Hz, 2H, H-30), 8.03 (d,
J¼8.5 Hz, 2H, H-30), 7.74 (d, J¼8.1 Hz, 1H, H-3), 7.54 (ddd, J¼8.3, 6.8,
and 1.4 Hz, 1H, H-5), 7.48 (m, 2H, H-4 and H-15), 7.34 (t, J¼7.4 Hz,
1H, H-14), 7.33 (d, J¼8.7 Hz, 1H, H-2), 7.28 (m, 2H, H-1 and H-13),
7.16 (d, J¼7.6 Hz,1H, H-12), 6.48 (s,1H, H-8), 5.82 (s,1H, H-15b), 2.94
(ddd, J¼ꢀ16.5, 11.8, and 6.4 Hz, 1H, H-11), 2.88 (ddd, J¼ꢀ12.1, 11.8,
and 4.3 Hz, 1H, H-10), 2.71 (ddd, J¼ꢀ12.1, 6.4, and 1.7 Hz, 1H, H-10),
and 2.61 (ddd, J¼ꢀ16.5, 4.3, and 1.7 Hz, 1H, H-11); 13C NMR
d 147.9
(C-40), 147.5 (C-6b), 144.8 (C-10), 134.6 (C-11a), 134.1 (C-15a), 133.5
(C-2a), 129.7 (C-15), 129.5 (C-12), 127.7 (C-20), 127.5 (2C, C-3 and C-
13), 126.3 (C-4), 125.5 (C-5), 125.3 (C-14), 125.1 (C-1), 124.4 (C-6a),
123.5 (C-30), 121.5 (C-6), 120.3 (C-2), 116.2 (C-15c), 90.4 (C-8), 60.2
(C-15b), 37.3 (C-10), and 28.6 (C-11). Anal. Calcd for C26H20N2O3: C,
76.46; H, 4.94; N, 6.86. Found: C, 76.32; H, 4.96; N, 6.90.
To a solution of thiourea 9, 10, 21 or 22 (1.00 mmol) in MeOH
(30 mL), MeI (0.60 mL, 10.00 mmol) was added and the solution
was stirred for 20 h. After evaporation of the solvent, the residue
was stirred in 3 M methanolic KOH (30 mL) for 4 h. Following
evaporation, H2O (30 mL) was added to the residue and the mixture
was extracted with CHCl3 (3ꢂ30 mL). After drying (Na2SO4) and
evaporation of the solvent, the crystalline oxazine was obtained on
treatment with n-hexane (20 mL); it was filtered off and recrys-
tallized from n-hexane–i-Pr2O (3:1).
4.5. General method for the synthesis of N1-[1-(2-hydroxy-1-
naphthyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline]-N2-
p-chlorophenylthiourea (9), N1-[1-(2-hydroxy-1-naphthyl)-
1,2,3,4-tetrahydroisoquinoline]-N2-p-chlorophenylthiourea
(10), N1-[1-(1-hydroxy-2-naphthyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline]-N2-p-chlorophenylthiourea (21), and
N1-[1-(1-hydroxy-2-naphthyl)-1,2,3,4-
4.6.1. Compound 11
Yield: 0.26 g (55%). Mp 158–160 ꢁC. 1H NMR
d
7.89 (d, J¼8.1 Hz,
1H, H-4), 7.84 (d, J¼8.7 Hz, 1H, H-1), 7.83 (d, J¼8.5 Hz, 1H, H-5), 7.59
(t, J¼7.7 Hz, 1H, H-2), 7.49 (t, J¼7.5 Hz, 1H, H-3), 7.21 (d, J¼8.6 Hz,
2H, H-30), 7.11 (d, J¼8.9 Hz, 1H, H-6), 6.99 (d, J¼8.6 Hz, 2H, H-20),
6.72 (s, 1H, H-12), 6.21 (s, 1H, H-15), 6.08 (s, 1H, H-15b), 4.68 (ddd,
J¼12.8, 6.6, and 2.1 Hz, 1H, H-10), 3.86 (s, 3H, OMe-13), 3.70 (ddd,
J¼16.4, 10.4, and 6.3 Hz, 1H, H-11), 3.60 (ddd, J¼12.4, 11.4, and
tetrahydroisoquinoline]-N2-p-chlorophenylthiourea (22)
A mixture of 1-hydroxynaphthyltetrahydroisoquinoline 1, 2, 13
or 14 (1.82 mmol) and phenyl isothiocyanate (0.30 mL, 2.00 mmol)
in abs toluene (50 mL) was stirred at room temperature for 24 h. The
crystals that separated out were filtered off, washed with toluene
(2ꢂ20 mL), and used in the next step without further purification.
5.1 Hz, 1H, H-10), 3.29 (s, 3H, OMe-14), and 2.81 (m, 1H, H-11); 13
C
NMR d
148.6 (C-13),146.9 (C-6a),146.9 (C-14),145.7 (C-10),145.5 (C-
8), 130.9 (C-15d), 130.3 (C-4a), 130.1 (C-5), 128.9 (C-4), 128.4 (C-30),
127.8 (C-15a), 127.4 (C-2), 127.2 (C-11a or C-40), 127.1 (C-40 or C-11a),
124.9 (C-3), 124.9 (C-20), 122.8 (C-1), 116.8 (C-6), 113.9 (C-15c), 112.2
(C-12), 109.5 (C-15), 55.9 (OMe-13), 55.6 (OMe-14), 54.1 (C-15b),
45.7 (C-10), and 24.5 (C-11). Anal. Calcd for C28H23ClN2O3: C, 71.41;
H, 4.92; N, 5.95. Found: C, 71.57; H, 4.93; N, 5.93.
4.5.1. Compound 9
Yield: 0.87 g (95%). Mp 154–155 ꢁC. 1H NMR
d 8.01 (br s, 1H),
7.81 (m, 3H), 7.41 (s, 1H), 7.32 (m, 2H), 7.11 (m, 2H), 7.05 (d,
J¼8.6 Hz, 2H), 6.92 (d, J¼8.6 Hz, 2H), 6.76 (s, 1H), 6.38 (s, 1H), 4.72
(m, 1H), 3.91 (s, 3H), 3.87 (m, 2H), 3.55 (s, 3H), 3.31 (m, 1H), and
2.92 (m, 1H). Anal. Calcd for C28H25ClN2O3S: C, 66.59; H, 4.99; N,
5.55. Found: C, 66.72; H, 5.02; N, 5.61.
4.6.2. Compound 12
Yield: 0.25 g (61%). Mp 223–225 ꢁC. 1H NMR
d
7.89 (d, J¼8.1 Hz,
1H, H-4), 7.83 (d, J¼8.9 Hz, 1H, H-5), 7.77 (d, J¼8.4 Hz, 1H, H-1), 7.57
(t, J¼7.5 Hz, 1H, H-2), 7.49 (t, J¼7.4 Hz, 1H, H-3), 7.21 (m, 4H, H-12,
H-13, and H-30), 7.10 (d, J¼8.9 Hz, 1H, H-6), 6.97 (d, J¼8.6 Hz, 2H, H-
20), 6.93 (t, J¼7.5 Hz, 1H, H-14), 6.63 (d, J¼7.8 Hz, 1H, H-15), 6.10 (s,
1H, H-15b), 4.66 (m, 1H, H-10), 3.69 (m, 2H, H-10 and H-11), and
4.5.2. Compound 10
Yield: 0.78 g (97%). Mp 149–151 ꢁC. 1H NMR
d 8.06 (br s,1H), 7.87
(m, 2H), 7.68 (m, 1H), 7.29 (m, 4H), 7.12 (m, 3H), 7.04 (d, J¼8.7 Hz,
2H), 6.87 (d, J¼8.7 Hz, 2H), 6.79 (d, J¼7.9 Hz, 1H), 5.04 (m, 1H), 3.88
(m, 1H), 3.32 (m, 2H), and 3.04 (m, 1H). Anal. Calcd for
2.94 (m, 1H, H-11); 13C NMR 146.9 (C-6a), 145.7 (C-10), 145.4 (C-8),
d
C
6.32.
26H21ClN2OS: C, 70.18; H, 4.76; N, 6.30. Found: C, 70.27; H, 4.72; N,
136.1 (C-15a), 135.1 (C-11a), 131.0 (C-15d), 130.3 (C-4a), 130.2 (C-5),
129.3 (C-12), 128.8 (C-4), 128.4 (C-30), 127.6 (C-2), 127.1 (C-40), 126.0
(C-14), 125.6 (C-15), 125.0 (C-3), 124.9 (C-20), 122.8 (2C, C-1 and C-
13), 116.7 (C-6), 113.7 (C-15c), 54.2 (C-15b), 45.4 (C-10), and 25.1 (C-
11). Anal. Calcd for C26H19ClN2O: C, 76.00; H, 4.66; N, 6.82. Found: C,
76.18; H, 4.62; N, 6.84.
4.5.3. Compound 21
Yield: 0.83 g (90%). Mp 135–137 ꢁC. 1H NMR (DMSO-d6)
d 10.27
(br s, 1H), 9.85 (br s, 1H), 8.30 (m, 1H), 7.81 (m, 1H), 7.52 (m, 2H),

M. Heydenreich et al. / Tetrahedron 64 (2008) 7378–7385
7385
803–809; (c) Soha´r, P.; La´za´r, L.; Fu¨lo¨p, F.; Berna´th, G.; Ko´ bor, J. Tetrahedron
¨lo¨p, F.; Martinek, T. A.; Berna´th, G. ARKIVOC 2001,
iii, 33–39; (e) Heydenreich, M.; Koch, A.; La´za´r, L.; Szatma´ri, I.; Sillanpa¨a¨, R.;
Kleinpeter, E.; Fu¨ lo¨p, F. Tetrahedron 2003, 59, 1951–1959.
3. Soha´r, P.; Forro´ , E.; La´za´r, L.; Berna´th, G.; Sillanpa¨a¨, R.; Fu¨lo¨p, F. J. Chem. Soc.,
Perkin Trans. 2 2000, 287–294.
4.6.3. Compound 23
1992, 48, 4937–4948; (d) Fu
Yield: 0.31 g (65%). Mp 238–240 ꢁC. 1H NMR
d
7.83 (d, J¼8.0 Hz,
1H, H-3), 7.80 (d, J¼8.2 Hz, 1H, H-6), 7.66 (d, J¼8.4 Hz, 1H, H-2), 7.51
(t, J¼7.9 Hz, 1H, H-4), 7.47 (t, J¼8.3 Hz, 1H, H-5), 7.37 (d, J¼8.4 Hz,
1H, H-1), 7.29 (d, J¼8.6 Hz, 2H, H-30), 7.08 (d, J¼8.6 Hz, 2H, H-20),
6.72 (s, 1H, H-12), 6.61 (s, 1H, H-15), 5.67 (s, 1H, H-15b), 4.65 (m, 1H,
H-10), 3.88 (s, 3H, OMe-13), 3.69 (s, 3H, OMe-14), 3.51 (m, 2H, H-10
´
¨
¨ ¨
¨ ¨
4. (a) Martinek, T. A.; Forro, E.; Gunther, G.; Sillanpaa, R.; Fulop, F. J. Org. Chem.
2000, 65, 316–321; (b) Fu¨lo¨p, F.; Forro´ , E.; Martinek, T. A.; Gu¨nther, G.; Sillan-
pa¨a¨, R. J. Mol. Struct. 2000, 554, 119–125.
and H-11), and 2.75 (m, 1H, H-11); 13C NMR
d 148.5 (C-13), 147.2 (C-
5. Zala´n, Z.; Martinek, T. A.; La´za´r, L.; Fu¨lo¨p, F. Tetrahedron 2003, 59, 9117–9125.
6. Zala´n, Z.; Martinek, T. A.; La´za´r, L.; Sillanpa¨a¨, R.; Fu¨ lo¨p, F. Tetrahedron 2006, 62,
2883–2891.
14), 146.0 (C-8), 145.8 (C-10), 144.3 (C-6b), 133.8 (C-2a), 128.4 (C-30),
127.6 (C-3), 127.3 (C-11a or C-40), 127.2 (C-40 or C-11a), 127.1 (C-15a),
126.9 (C-4 or C-5), 126.8 (C-5 or C-4), 124.9 (C-20), 123.9 (C-1), 123.5
(C-6a), 123.1 (C-2), 121.1 (C-6), 116.0 (C-15c), 112.1 (C-12), 109.0 (C-
15), 56.1 (C-15b), 55.9 (OMe-13), 55.9 (OMe-14), 44.8 (C-10), and
25.4 (C-11). Anal. Calcd for C28H23ClN2O3: C, 71.41; H, 4.92; N, 5.95.
Found: C, 71.61; H, 4.95; N, 5.97.
7. (a) Wanner, K. T.; Praschak, I.; Ho¨fner, G.; Beer, H. Arch. Pharm. Pharm. Med.
Chem. 1996, 329, 11–22; (b) Yoneda, R.; Sakamoto, Y.; Oketo, Y.; Harusawa, S.;
Kurihara, T. Tetrahedron 1996, 52, 14563–14576; (c) Manini, P.; d’Ischia, M.;
Lanzetta, R.; Parrilli, M.; Prota, G. Bioorg. Med. Chem. 1999, 7, 2525–2530; (d)
Ohtake, H.; Imada, Y.; Murahashi, S.-I. J. Org. Chem. 1999, 64, 3790–3791.
8. (a) Szatma´ri, I.; La´za´r, L.; Fu¨lo¨p, F. Tetrahedron Lett. 2006, 47, 3881–3883; (b)
MacLeod, P. D.; Li, Z.; Feng, J.; Li, C.-J. Tetrahedron Lett. 2006, 47, 6791–6794.
9. Altona, C.; Francke, R.; de Haan, R.; Ippel, J. H.; Daalmans, J.; Westra Hoekzema,
A. J. A.; van Wijk, J. Magn. Reson. Chem. 1994, 32, 670–678.
10. PERCH Solutions Ltd. Kuopio, Finland Laatikainen, R. J. Magn. Reson. 1991, 92,
1–9; Laatikainen, R. QCMP100. MLDC8 QCPE Bull. 1992, 12, 23; Laatikainen, R.;
Niemitz, M.; Weber, U.; Sundelin, J.; Hassinen, T.; Vepsa¨la¨inen, J. J. Magn. Reson.
1996, A120, 1–10; Laatikainen, R.; Niemitz, M.; Malaisse, W. J.; Biesemans, M.;
Willem, R. Magn. Reson. Med. 1996, 36, 359–365.
4.6.4. Compound 24
Yield: 0.24 g (58%). Mp 224–227 ꢁC. 1H NMR
d
8.27 (d, J¼7.1 Hz,
1H), 7.66 (d, J¼7.9 Hz, 1H), 7.11–7.39 (m, 9H), 6.98 (d, J¼8.6 Hz, 1H),
6.86 (d, J¼7.5 Hz, 1H), 6.72 (d, J¼8.4 Hz, 1H), 4.63 (m, 1H), 3.35 (m,
3H), and 2.87 (d, J¼15.1 Hz, 1H); this compound decomposes very
rapidly in solution, and therefore no 13C NMR data are available.
Anal. Calcd for C26H19ClN2O: C, 76.00; H, 4.66; N, 6.82. Found: C,
76.11; H, 4.68; N, 6.81.
11. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J.
V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Lia-
shenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
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Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision C.02;
Gaussian: Wallingford, CT, 2004.
Acknowledgements
The authors’ thanks are due to the Hungarian Research Foun-
dation (OTKA No. D48669) for financial support.
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